1. Field of the Invention
This invention relates to camptothecin compounds which inhibit the enzyme topoisomerase I and alkylate deoxyribonucleic acid (DNA) in association with topoisomerase I. Camptothecin compounds have the ring structure shown below. ##STR1## The invention also relates to the treatment of tumors in animals with camptothecin compounds.
2. Background of the Invention
Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid which is known to inhibit the enzyme topoisomerase I and is a potent anti-tumor agent. Camptothecin was isolated from the wood and bark of Camptotheca acuminata by Wall et al. (Wall et al., 1966, J. Am. Chem. Soc., 88:3888).
U.S. Pat. No. 4,894,456 describes methods of synthesizing camptothecin compounds which act as inhibitors of topoisomerase I and are effective in the treatment of leukemia (L-1210). U.S. Pat. No. 5,225,404 discloses methods of treating colon tumors with camptothecin compounds.
Numerous camptothecin compounds and their use as inhibitors of topoisomerase I are taught by U.S. Pat. No. 5,053,512; U.S. Pat. No. 4,981,968; U.S. Pat. No. 5,049,668; U.S. Pat. No. 5,106,742; U.S. Pat. No. 5,180,722; U.S. Pat. No. 5,244,903; U.S. Pat. No. 5,227,380; U.S. Pat. No. 5,122,606; U.S. Pat. No. 5,122,526; and U.S. Pat. No. 5,340,817.
Naturally occurring camptothecin has the 20(S)-configuration and has been shown to inhibit both DNA and RNA synthesis and to cause reversible fragmentation of DNA in cultured mammalian cells (Hsiang et al., 1989, Cancer Research, 49:4385-4389). When the camptothecin is removed, the inhibition of high molecular weight RNA synthesis is reversed, whereas there was only a partial restoration of DNA synthesis.
The enzyme topoisomerase I has been identified as the cellular target of camptothecin compounds. The enzyme has been implicated in various DNA transactions such as replication, transcription and recombination. Topoisomerase I relaxes both positively and negatively supercoiled DNA. The enzyme mechanism is believed to involve a transient breakage of one of the two DNA strands and the formation of a reversible covalent topoisomerase I enzyme-DNA complex. Camptothecin interferes with the DNA breakage-reunion reaction by reversibly trapping the enzyme-DNA intermediate termed the "cleavable complex" by Hsiang et al., Id. The high levels of topoisomerase I in several types of human cancer and the low levels in correspondingly normal tissue provide the basis for tumor treatment with biologically active camptothecin analogs.
A need continues to exist, however, for camptothecin compounds having improved activity.